title: SAR profiles of spirocyclic nicotinamide derived selective HDAC1/HDAC2 inhibitors (SHI-1:2).
abstract: A potent family of spirocyclic nicotinyl aminobenzamide selective HDAC1/HDAC2 inhibitors (SHI-1:2) is profiled. The incorporation of a biaryl zinc-binding motif into a nicotinyl scaffold resulted in enhanced potency and selectivity versus HDAC3, but also imparted hERG activity. It was discovered that increasing polar surface area about the spirocycle attenuates this liability. Compound 12 induced a 4-fold increase in acetylated histone H2B in an HCT-116 xenograft model study with acute exposure, and inhibited tumor growth in a 21-day efficacy study with qd dosing.
authors.affiliation: Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. joey_methot@merck.com
authors.forename: Joey L
authors.initials: JL
authors.lastname: Methot
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Hamblett
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Mampreian
authors.forename: Joon
authors.initials: J
authors.lastname: Jung
authors.forename: Andreas
authors.initials: A
authors.lastname: Harsch
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Szewczak
authors.forename: William K
authors.initials: WK
authors.lastname: Dahlberg
authors.forename: Richard E
authors.initials: RE
authors.lastname: Middleton
authors.forename: Bethany
authors.initials: B
authors.lastname: Hughes
authors.forename: Judith C
authors.initials: JC
authors.lastname: Fleming
authors.forename: Hongmei
authors.initials: H
authors.lastname: Wang
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Kral
authors.forename: Nicole
authors.initials: N
authors.lastname: Ozerova
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Cruz
authors.forename: Brian
authors.initials: B
authors.lastname: Haines
authors.forename: Melissa
authors.initials: M
authors.lastname: Chenard
authors.forename: Candia M
authors.initials: CM
authors.lastname: Kenific
authors.forename: J Paul
authors.initials: JP
authors.lastname: Secrist
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Miller
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones / Q000032:analysis; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009536:Niacinamide / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020033:Protein Isoforms; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays; D000099186:Histone Deacetylase 3
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D009536:Niacinamide; D020033:Protein Isoforms; D013141:Spiro Compounds; D000099186:Histone Deacetylase 3; C000606913:KCNH2 protein, human